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Thursday, June 26, 2008

Betting on a Cure

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Could drug therapy curb an addiction to gambling?

This summer, two scientists are making a risky bet: that they can treat gambling addiction solely by administering drugs. Both researchers have just begun small trials of pharmacotherapies traditionally used for treating alcoholism. They hypothesize that gambling releases the same kind of feel-good chemicals that alcohol does, and that the drugs may tamp down the thrill of betting just enough to help "problem gamblers" resist the allure.

So far, the early results are encouraging—and that's saying something, given that the trials recruited patients for the express purpose of taking the drugs and then exposing themselves to temptation. But doctors have been trying to treat gamblers with similar therapies for years, with mixed results at best. Can these researchers succeed where past attempts have failed? Or are they still a few cards short of a good hand?

The first of this summer's two trials is the brainchild of Judy Grisel, a psychologist at Furman University in Greenville, S.C. The legwork for it began several years ago, when Grisel sent a student into video gambling parlors along the northwestern border of South Carolina. ("She smelled like smoke for three straight months," Grisel says.) The student gave 60 of the regulars at the gaming parlors $50 in exchange for letting her watch while they played a game called Shamrock 7s—a variation of video poker that is "a very repetitive, mind-numbing game, with no strategy," says Grisel. Half of the gamblers took a placebo. The other half took a drug called Naltrexone, which is approved for treating alcoholism and drug addiction.

"People who take the drug tend to drink more slowly and leave bars earlier," says Grisel. "They say things like, 'Well, I've got a lot going on tomorrow,' or 'I had a long week.' They don't seem to enjoy drinking as much." Naltrexone works by blocking opiate receptors—a crucial step in the pathway for processing dopamine, the pleasure neurotransmitter that activates the brain's sense of reward. Essentially, the drug is designed to keep people from enjoying addictive behaviors as much as they normally might.

Sure enough, Grisel and her student found that those gamblers who took Naltrexone weren't nearly as active in the parlors as the control group was. "They bet about half as much money," she says. "It wasn't a knock-your-socks-off effect, but it was significant." Alas, any hopes for identical follow-up tests were thwarted: Shortly after the experiment, South Carolina outlawed video gambling parlors. So this summer, Grisel and another student will try to replicate the results with Naltrexone in the lab. Her second student has designed a computer-based card game and will watch to see whether gamblers taking Naltrexone are less willing to risk large amounts of money while playing.

Meanwhile, a similar trial is getting under way across the country at the University of Nebraska Medical Center. Dennis McNeilly, a psychiatrist at the UNMC, has built his experiment around Acamprosate, which has a different mechanism of action than Naltrexone but is also designed to decrease cravings for alcohol. A recent small study found that it could also cut back on behaviors tied to problems of impulse control, such as compulsive eating, in some patients.

McNeilly plans to recruit about 20 people who are healthy except for their gambling addictions, people who "have truly tried to stop gambling, but can't," he says. (His experiment has no control group, which means that his results won't be conclusive, but they could potentially point the way for further research.) He will give all of his gamblers Acamprosate three times a day for eight weeks, and then ask them to evaluate their cravings in that time period. "These are individuals who arrange their days and their lifestyles around gambling. They are thinking about it all day long," he says. "So we'll want to see if they still plan their days around it, and if they actually do bet less. We want to know how people experience taking this drug: What kind of difference does it make in their lives? The whole idea is that ultimately we want to help people get to a point where they can have fewer cravings so they can say, 'Gee, this isn't as much fun anymore.'"

There are two main problems the trials might run into: Either the drugs won't work, or they'll work a little too well. The first objection is backed up by other studies that have shown that drugs designed to tamp down urges may have limited success. Studies of Acamprosate have shown that when the drug works in alcoholics, it does so only if used in combination with counseling and group therapy. And studies of Naltrexone have gone both ways: Some paint it as a huge success, but others are more skeptical. One recent trial published in the Journal of Clinical Psychiatry found that almost 40 percent of patients who took Naltrexone managed not to gamble for at least a month (the placebo rate was a comparatively measly 10 percent). But another trial of Naltrexone and gamblers, published in the Annals of Clinical Psychiatry in 2002, found that the drug was less likely to help "patients with poorer social and occupational functioning due to urges and thoughts about gambling"—in other words, those who need help the most.

Mark Stacy, a neurologist at Duke University, says he's tried using this type of drug in Parkinson's patients, who sometimes develop compulsive gambling behaviors as a result of medications that boost their dopamine levels. (In Parkinson's, the brain's dopamine-producing neurons atrophy and die, so many drugs used to treat the illness affect the dopamine "pleasure" pathways, often with unexpected results.) "Nothing really seems to work [to treat gambling addiction in those patients]," he says. "We've never been able to treat compulsivity very well."

Part of the problem, according to Stacy, is that drugs like Naltrexone are targeting the "D2" dopamine pathway in the brain, which is associated with rewards, but not another pathway, "D1," which is more closely associated with compulsive behaviors. "The next wave of addiction treatments," he says, will need to attack both pathways instead of "just going after one neurotransmitter constellation." It's possible, he adds, that just going after the D2 dopamine pathway could make gambling problems even worse, since the compulsion pathway will still be open for business.

The second objection—that dopamine blockers might work too well—centers on the basic mechanism of Naltrexone, which is a crude one. Because it works by stopping the brain from processing the chemical that makes an activity feel good, it could cause some patients to lose pleasure in other areas of life. Studies show that Naltrexone treatment doesn't trigger depression in most patients, but Grisel says that the drug might make some of life's most fun activities seem "gray and uninspiring" to former addicts. "If someone's just sitting at their desk having a regular day and they took this drug, they wouldn't be able to tell a difference," she says. "But if they were about to have sex or listening to a concert by their favorite band, they probably wouldn't enjoy that as much."

Ultimately, that may turn out to be the biggest problem with these drugs. Forget for a minute how well they work: If losing the capacity to experience joy is a risk, what patient would be willing to take them?